Neurodevelopmental dysregulation of catecholamine neurotransmission in the forebrain contributes to the pathogenesis of neurological and neuropsychiatric disorders, even though clinical phenotypes usually become apparent only later in life. We hypothesize that abnormalities in dopamine signaling initiated developmentally may result in life-long changes in the activation of dopamine-modulated intracellular signaling cascades and underlie neurobehavioral changes observed in adults following disrupted dopamine neurotransmission. We propose two specific aims to test the hypothesis that developmental abnormalities in dopamine D1 receptor signaling result in long-lasting changes in basal and/or receptor-induced activation of dopamine-modulated signaling components. We will investigate changes in phosphorylation of the molecular substrates DARPP-32, CaMKII and the AMPA receptor GluR1 subunit because of their key role in modulating excitatory synaptic transmission in dopaminoceptive brain regions. Aim 1 serves to investigate changes in basal activation of these substrates in a genetic model of constitutive loss of D1 receptor signaling in knockout mice and in hypomorphic models of D1 receptor signaling: rabbits exposed to cocaine in utero, a model in which there is a pharmacologically induced reduction in D1 receptor expression at the cell-surface for signal transduction but not complete loss of D1 receptor signaling, and in D1 receptor haploinsufficient mice. Aim 2 then investigates activation of DARPP-32, CaMKII, and the glutamate receptor GluR1 subunit in cocaine-exposed progeny following D1 receptor stimulation with selective D1 receptor -like agonists and psychostimulant drugs. The elucidation of differential regulatory mechanisms when D1 receptor signaling is diminished in the hypomorphic models compared to complete loss of D1 receptor signaling in the knockout mice will inform our understanding of complex (mal)adaptations to neurodevelopmental insults. In addition, these studies will inform our understanding of the molecular alterations induced by developmental disruptions of dopamine neurotransmission, and how these changes contribute to dysfunctions in neuronal activity and behavior. Beyond the direct issue of understanding (mal)adaptive changes after cocaine exposure in utero within clinical populations of exposed individuals, these studies also hold more general importance for understanding the long-term consequences of how neural networks adapt to developmental disruptions in dopamine signaling. PUBLIC HEALTH RELEVANCE: Dysfunctions in brain catecholamine systems have been linked to both the development and expression of mental illness. The studies contained in this proposal will help elucidate how dysregulation of the neurochemical dopamine contributes to (mal)adaptive alterations in cell signaling and the establishment of abnormal forebrain circuitry.